Compounds and pharmaceutical compositions of the present invention of this type are useful in the prevention or treatment of various disorders. For instance, the substituted 4-phenyltetrahydroisoquinoline compounds and pharmaceutical compositions comprising them which are excellent inhibitors of the sodium-hydrogen exchanger (NHE) are of surprising therapeutic value in the treatment of respiratory disorders, including snoring, as well as improvement of the respiratory drive. The NHE-3 inhibitor compounds are also useful in the treatment of acute and chronic disorders of the kidneys and of the intestines, disorders resulting from ischemic and/or reperfusion events, as well as those resulting from proliferative or fibrotic events, the treatment or prophylaxis of disorders of the central nervous system, of lipid metabolism and of diabetes, of blood coagulation and of infestation by parasites.
The NHE3 inhibitors known in the prior art hitherto are derived, for example, from compounds of the acylguanidine type (EP825178), norbornylamine types (WO0144164), 2-guanidinoquinazoline type (WO0179186), benzamidine type (WO0121582, WO0172742) or tetrahydroisoquinoline type (WO03048129, WO03055880). The squalamine which has likewise been described as an NHE3 inhibitor (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45):C136-C144), according to the current state of knowledge, does not act directly like the compounds of the formula I or II, but rather via an indirect mechanism and thus does not achieve its maximum strength of action until after one hour. Such NHE3 inhibitors having different types of mechanistic action are suitable, for example, as combination partners of the present inventive compounds.
Clonidine, which is distantly related to the inventive compounds, is known to be a weak NHE inhibitor. However, its action on the NHE3 of the rat is extremely moderate at a half-maximum inhibitory concentration (IC50) of 620 μM. Instead, it has a certain selectivity for the NHE2 (J. Orlowski et al. J. Biol. Chem. 268, 25536). It should therefore be referred to rather as an NHE2 inhibitor. In addition to the weak NHE action, clonidine has a high affinity for the adrenergic alpha2 receptor and imidazoline I1 receptor, which causes strong blood sugar-lowering action (Ernsberger et al. Eur. J. Pharmacol. 134, 1, 1987).
Compounds which are similar to clonidine but have a thiophene instead of the phenyl ring are disclosed in DE1941761. The structures of formula I disclosed and claimed herein differ from existing compounds by the fusing of a thieno-substituent to the imidazole moiety of the formula I or II. This distinction allows the above-described clonidine-like undesired cardiovascular effects mediated by alpha-adrenoreceptor action to be eliminated. At the same time, as a consequence of the substitution differences, the NHE-inhibiting properties of the compounds described here are enhanced down to the micromolar and submicromolar range, while the compounds disclosed by DE1941761 exhibit only very weakly pronounced NHE-inhibiting effects, if any. For instance, the hypotensive compound described in the application DE1941761, tiamenidine, in a therapeutically utilizable concentration range, has no relevant inhibitory actions on any of the NHE subtypes investigated, NHE1, NHE2, NHE3 and NHE5. The application WO03053434 proposes NHE3 inhibitors of the imidazoline type, the patent application WO 03101984 of the thiophene type and the application DE10304374 of the imidazole type.
Previously disclosed NHE3 inhibitors are derived for example from compounds of the acylguanidine type (EP825178), norbornylamine type (WO0144164), 2-guanidinoquinazoline type (WO0179186) or benzamidine type (WO0121582, WO017242). Squalamine, which is likewise described as an NHE3 inhibitor (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45):C136-C144) does not according to the current state of knowledge act immediately like the compounds of the formula I, but acts via an indirect mechanism and thus reaches its maximum strength of effect only after one hour. Such NHE3 inhibitors acting via different mechanism are suitable for example as combination partners for the present compounds of the invention.
Tetrahydroisoquinolines as inhibitors of the sodium-hydrogen exchanger of subtype 3 (NHE3) have been described in the applications WO03048129 and DE10312963. The patent application WO03055880 describes the related class of tetrahydroisoquinolinium salt compounds as NHE3 inhibitors. It has now been found, surprisingly, that the compounds of the formula I described herein are likewise potent inhibitors of NHE3 and moreover have advantageous pharmacological and pharmacokinetic properties. Thus, the compounds are notable for improved properties such as, for example, a high selectivity for the sodium-hydrogen exchanger with a negligible effect on hERG potassium channels.
NHE3 is found in the body of various species preferentially in the bile, the intestine and the kidney (Larry Fliegel et al., Biochem. Cell. Biol. 76:735-741, 1998), but has also been detected in the brain (E. Ma et al., Neuroscience 79:591-603).
On the basis of the NHE-inhibitory properties, the 4-phenyltetrahydroisoquinoline compounds of the present invention as defined by formula I herein and their pharmaceutically acceptable salts are suitable for the prevention and treatment of diseases which are caused by activation or by an activated NHE, and of diseases which are caused secondarily by the NHE-related damage.
Optionally, the NHE inhibitors described herein can be combined with other compounds which also regulate the intracellular pH environment Suitable combination comprise the formulation with other inhibitors of the enzyme group of carbonic anhydrases and inhibitors of the transport systems that carry bicarbonate ions, such as of the sodium-bicarbonate co-transporter (NBC) or of the sodium-dependent chloride-bicarbonate exchanger, and with other NHE inhibitors with an inhibitory effect on other NHE subtypes, because the pharmacologically relevant pH-regulating effects of the NHE inhibitors described herein can be enhanced or modulated thereby.
The use of compounds of the present invention relates to the prevention and the treatment of acute and chronic diseases in veterinary and human medicine.
The pharmacological effect of the compounds of the formula I is characterized in that they lead to an improvement in the respiratory drive. They can therefore be used for the treatment of impaired respiratory
In the present invention, it has surprisingly been possible to show that the compounds of formula I, below, constitute potent inhibitors of sodium/proton exchange (NHE), especially of sub-type 3 sodium/proton exchanger (NHE3).